Triple-negative breast cancer

Triple-negative breast cancer (sometimes abbreviated TNBC) is any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) and HER2/neu.[1] This makes it more difficult to treat since most hormone therapies target one of the three receptors, so triple-negative cancers often require combination therapies. Triple negative is sometimes used as a surrogate term for basal-like; however, more detailed classification may provide better guidance for treatment and better estimates for prognosis.[2]

Triple-negative breast cancers comprise a very heterogeneous group of cancers. There is conflicting information over prognosis for the various subtypes, but it appears that the Nottingham prognostic index is valid and hence general prognosis is rather similar with other breast cancer of same stage, except that more aggressive treatment is required.[3] Some types of triple-negative breast cancer are known to be more aggressive, with poor prognosis, while other types have very similar or better prognosis than hormone receptor positive breast cancers.[4] Among breast cancer patients, 15–20% of women have been diagnosed as triple-negative, while the majority of TNBC patients have been found to be young women or women with a mutation in the BRCA1 gene.[5] Pooled data of all triple-negative subtypes suggests that, with optimal treatment, 20-year survival rates are very close to those of hormone positive cancer.[2]

Triple-negative breast cancers have a relapse pattern that is very different from hormone-positive breast cancers: the risk of relapse is much higher for the first 3–5 years, but drops sharply and substantially below that of hormone-positive breast cancers afterwards. This relapse pattern has been recognized for all types of triple-negative cancers for which sufficient data exist, although the absolute relapse and survival rates differ across subtypes.[2][4]

Cause

One known cause of triple negative breast cancer is germline mutations. These are alterations within the heritable lineage that is being passed down to the offspring. Fifteen percent of TNBC can be traced back to germline mutations that are within the BRCA1 and BRCA2 genes (Song 2014). Due to their high disposition for cancers of the breast, ovaries, pancreas, and prostate, the BRCA1 and BRCA2 genes were identified as high risk for triple-negative (Pruss 2014). Changes or mutations in 19p13.1 and MDM4 loci have also been associated with triple negative breast cancer, but not other forms of breast cancer. Thus, triple negative tumors may be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline alterations (Kristen 2013).

Classification

Triple-negative breast cancers (TNBC) are sometimes classified into "basal-type" and other cancers; however, there is no standard classification scheme. Basal type cancers are frequently defined by cytokeratin 5/6 and EGFR staining. However, no clear criteria or cutoff values have been standardized yet.[2] About 75% of basal-type breast cancers are triple negative.

Some TNBC overexpress epidermal growth factor receptor (EGFR)[6][7] or transmembrane glycoprotein NMB (GPNMB).

Upon histologic examination, triple-negative breast tumors mostly fall into the categories of secretory cell carcinoma or adenoid cystic types (both considered less aggressive); medullary cancers and grade 3 invasive ductal carcinomas with no specific subtype; and highly aggressive metastatic cancers.[2] Medullary TNBC in younger women are frequently BRCA1-related.

Rare forms of triple-negative breast cancer are apocrine and squamous carcinoma. Inflammatory breast cancer is also frequently triple negative.

Many proteins such as Caveolin 1/2, Survivin are researched as possible classification or prognostic factors.

TNBCs have been classified using an integrative analysis of cancer genomics data (DNA copy number, DNA methylation, and mRNA) and PPI data from a prognostic point of view, and several key subnetworks (i.e. ubiquitin/proteasome, complement system, metabolism-related Warburg effect, ER-Golgi-cell surface trafficking, transcription) significantly related to patient survival have been identified.[8]

Treatment

Standard treatment is surgery with adjuvant chemotherapy and radiotherapy. As a variation, neoadjuvant chemotherapy is very frequently used for triple-negative breast cancers as they are more susceptible to platinum-based regimen, allowing for a higher rate of breast-conserving surgeries. Important details on the individual responsiveness of particular cancers can be gained from evaluating the response to this form of chemotherapy. However, the improvement in breast conservation is only 10–15% and the clues to individual responsiveness have conclusively proven to make an improvement in outcomes.

TNBCs are generally very susceptible to chemotherapy. In some cases, however, early complete response does not correlate with overall survival. This makes it particularly complicated to find the optimal chemotherapy. Adding a taxane to the chemotherapy appears to improve outcome substantially.[2][9]

BRCA1-related triple-negative breast cancer appear to be particularly susceptible to chemotherapy, including platinum-based agents and taxanes.

Although mutations in single genes were not individually predictive, TNBC tumors bearing mutations in genes involved in the androgen receptor (AR) and FOXA1 pathways were much more sensitive to chemotherapy. Mutations in the AR/FOXA1 pathway provide a novel marker for identifying chemosensitive TNBC patients who may benefit from current standard-of-care chemotherapy regimens. Mutations that lowered the levels of functional BRCA1 or BRCA2 RNA were associated with significantly better survival outcomes. This BRCA deficience signature define a new, highly chemosensitive subtype of TNBC. BRCA-deficient TNBC tumors have a higher rate of clonal mutation burden, defined as more clonal tumors with a higher number of mutations per clone, and are also associated with a higher level of immune activation, which may explain their greater chemosensitivity.[10]

Trodelvy™ (sacituzumab govitecan), an anti-Trop-2 antibody linked to SN-38, developed by Immunomedics Inc. (now Gilead Sciences) was approved by the FDA on 22 April 2020 for the treatment of metastatic TNBC.[11] Trodelvy™ had previously received FDA priority review, breakthrough therapy, and fast track designations.[11]

Epidemiology

Triple-negative breast cancer accounts for approximately 15–25% of all breast cancer[12] cases. The overall proportion of TNBC is very similar in all age groups. Younger women have a higher rate of basal or BRCA related TNBC, while older women have a higher proportion of apocrine, normal-like and rare subtypes including neuroendocrine TNBC.[2]

A study in the US says that, among younger women, African American and Hispanic women have a higher risk of TNBC,[13] with African Americans facing worse prognosis than other ethnic groups.[14]

In 2009, a case-control study of 187 triple-negative breast cancer patients described a 2.5 increased risk for triple-negative breast cancer in women who used oral contraceptives (OCs) for more than one year, compared to women who used OCs for less than one year or never.[15] The increased risk for triple-negative breast cancer was 4.2 among women 40 years of age or younger who used OCs for more than one year, while there was no increased risk for women between the ages of 41 and 45. Also, as duration of OC use increased, triple-negative breast cancer risk increased.

Clinical research/trials

Angiogenesis and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown efficacy. Treatment modalities are not sufficiently established for normal use, and it is unclear in which stage they are best used and which patients would profit.

By 2009 A number of new strategies for TNBC were being tested in clinical trials,[7] including the PARP inhibitor BSI 201,[16] NK012.[17]

A novel antibody-drug conjugate known as Glembatumumab vedotin (CDX-011), which targets the protein GPNMB, has also shown encouraging clinical trial results in 2009.[18]

PARP inhibitors had shown some promise in early trials[16] but failed in some later trials.[19]

Nov 2013: An accelerated approval Phase II clinical trial (METRIC) investigating glembatumumab vedotin versus capecitabine has begun, expected to enroll 300 patients with GPNMB-expressing metastatic TNBC.[20]

Three early stage trials reported TNBC results in June 2016, for IMMU-132, Vantictumab, and atezolizumab in combination with the chemotherapy nab-paclitaxel.[21]

In 2019, CytoDyn initiated a Phase 1b/2 trial with its humanized monoclonal antibody, leronlimab (PRO 140), in combination with chemotherapy following strong results in animal murine models. Among other mechanisms of action, leronlimab is believed to inhibit metastasis by inhibiting the CCR5 receptor on cell surfaces, which is commonly expressed in triple-negative breast cancer. On November 11, 2019, CytoDyn reported that the first TNBC patient injected under its naïve protocol (not previously treated for triple-negative breast cancer) demonstrated significantly reduced levels of circulating tumor cells (CTCs) and decreased tumor size at two-week and five-week observation intervals compared to baseline observations. CTCs are a potential surrogate endpoint in oncology trials, with reduced levels suggesting long-term clinical benefit.[22][23]

Pre-clinical research/speculations

Triple-negative breast cancers (TNBC) have, on average, significantly higher fluorine-18 fluorodeoxyglucose (FDG) uptake (measured by the SUVmax values) compared with uptake in ER+/PR+/HER2- tumors using fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET).[24] It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology.

The widely used diabetes drug, metformin, holds promise for the treatment of triple-negative breast cancer.[25] In addition metformin may influence cancer cells through indirect (insulin-mediated) effects, or it may directly affect cell proliferation and apoptosis of cancer cells. Epidemiologic and preclinical lab studies indicate that metformin has anti-tumor effects, via at least two mechanisms, both involving activation of the AMP-activated protein kinase (AMPK). A large-scale phase III trial of metformin in the adjuvant breast cancer setting is being planned in 2009.[26]

Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study.[27]

See also

References
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Further reading
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